Cancer is one of the major causes of human morbidity and mortality. Cancer treatment is challenging because it is difficult to kill cancer cells without damaging or killing normal cells. Damaging or killing normal cells during cancer treatment causes adverse side effects in patients and can limit the amount of anticancer drug administered to a cancer patient. It is also difficult to kill cancer cells in regions distant from the vasculature where anticancer drugs fail to penetrate.
Many cancer cells are more hypoxic relative to normal cells. Tumor hypoxia is associated with resistance to anticancer therapies, cancer relapse, and poor prognosis. Certain drugs in preclinical and clinical development target hypoxic cancer cells. These drugs, called hypoxia-activated prodrugs or “HAPs” are administered in an inactive, or prodrug, form but are activated, and become toxic, in a hypoxic environment. PCT Pat. Pub. Nos. WO 07/002,931 and WO 08/083,101, each of which is incorporated herein by reference, describe HAPs such as those having a structure defined by Formula I, below.
where Z3 is selected from the group consisting of:
and X4 is Cl or Br. The compounds known as TH-302 and TH-281 are particularly promising therapeutic candidates. TH-302, known by the chemical name (2-bromoethyl)({[(2-bromoethyl)amino][(2-nitro-3-methyl imidazol-4-yl)methoxy]phosphoryl})amine, has the structure represented below:
See Duan et al., 2008, “Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs,” J Med. Chem. 51: 2412, incorporated herein by reference. Another promising HAP is TH-281, which differs from TH-302 only in that it has 2-chloroethyl groups instead of the 2-bromoethyl groups present in TH-302.
There remains a need for new methods of formulating HAPs such as TH-302 and TH-281 to improve their anticancer efficacy as well as methods for administering them, and other HAPs, alone and in combination with other anticancer agents, to improve cancer therapy. The present invention meets these needs.